The long-term objective of this proposal is to further our understanding of the cellular and subcellular mechanisms underlying the process of neuroimmunomodulation. Evidence has accumulated to support the idea that the nervous system interacts with the immune system. Results from anatomical, biochemical and physiological studies all suggest an effect of neural substance, neuropeptides, neurotransmitters and hormones, on several lymphocyte functions. An idea of the way these substances can modulate lymphocyte function is based on the observation that lymphocyte activation, mitogenesis and volume regulation are dependent on ionic fluxes, and neuropeptides and hormones that have been shown to modulate the immune response also modulate potassium and calcium channels in excitable cells. Thus, a possible mechanism by which the nervous system regulates the immune response is by modulating lymphocyte ion channels and currents. We therefore propose to study the effects of immunologically active transmitters, peptides and hormones on the ionic channels and currents of lymphocytes. The specific aims are: 1) Measure, using the whole cell configuration of the patch clamp technique (Hamil, et al., 1981), the electrical activity of murine and human T lymphocytes and study the modulation of this activity by neurotransmitters, neuropeptides and hormones. 2) Assess whether resting or proliferating T cells are more responsive to the applied neuromodulators. 3) Determine the second messenger system involved in the modulatory effect(s) observed. These studies will provide relevant information for our understanding of the signal transduction pathways involved in lymphocyte function and regulation and the design of immunosuppressive or immunoenhancing agents on the basis of their channel blocking properties.